Pirfenidone Treatment for Patients with Atypical Liver Function

ABSTRACT

Methods are provided for administering pirfenidone to a patient that has exhibited abnormal biomarkers of liver function in response to pirfenidone administration. The methods include administering to a patient pirfenidone at doses lower than the full target dosage for a time period, followed by administering to the patient pirfenidone at the full target dosage. The methods also include administering pirfenidone at the full target dose with no reduction and administering permanently reduced doses of pirfenidone.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. patent application Ser. No.12/488,228, filed Jun. 19, 2009, now abandoned, which claims the benefitof U.S. Pat. No. 7,566,729, filed Apr. 22, 2009, which claims priorityto U.S. Provisional Application Ser. No. 61/113,107, filed Nov. 10,2008, the disclosures of which are incorporated by reference in theirentirety. This application also claims the benefit of U.S. ProvisionalApplication Ser. No. 61/228,943, filed Jul. 27, 2009, the disclosure ofwhich is incorporated by reference in its entirety.

BACKGROUND

1. Field of the Disclosure

The disclosure relates generally to methods for reducing adverse effectsassociated with the treatment of diseases and disorders. Moreparticularly, the disclosure relates to methods for reducing abnormalliver function associated with 5-methyl-1-phenyl-2-(1H)-pyridone(“pirfenidone”) therapy.

2. Brief Description of Related Technology

U.S. Pat. Nos. 3,974,281, 4,042,699, and 4,052,509 generally relate topirfenidone administration. U.S. Pat. Nos. 5,310,562, 5,518,729, and5,716,632, all to Margolin and incorporated by reference herein, relateto pirfenidone administration.

Pulmonary fibrosis can be caused by a number of different conditions,including sarcoidosis, hypersensitivity pneumonitis, collagen vasculardisease, and inhalant exposure. Idiopathic pulmonary fibrosis (IPF) is adistinct entity, characterized by breathing difficulty, radiographicabnormalities, and progressive loss of lung function. It is invariablyprogressive, and carries a grave prognosis with a median life expectancyof 2-3 years.

Pirfenidone has been administered to IPF patients. In acompassionate-use study, Raghu et al. (“Treatment of idiopathicpulmonary fibrosis with a new antifibrotic agent, pirfenidone: resultsof a prospective, open-label phase II study.” Am J Respir Crit Care Med159:1061-1069, 1999) reported administration of pirfenidone. No adverseevents in hematology or blood chemistry were noted.

Nagai et al. conducted an uncontrolled, open-label study of pirfenidonein patients (“Open label compassionate use one year-treatment withpirfenidone to patients with chronic pulmonary fibrosis.” InternalMedicine 41:1118-1123, 2002). During treatment, no liver dysfunctions,hematologic abnormalities, or allergic or shock reactions were reported.

Moises et al. “A double-blind, multicenter study comparing pirfenidoneand prednisone for moderate-to-severe pulmonary fibrosis.” Chest124:116S, 2003 reported administration of pirfenidone.

Azuma et al. “Double-blind, placebo-controlled trial of pirfenidone inpatients with idiopathic pulmonary fibrosis.” Am J Respir Crit Care Med171:1040-1047, 2005) describes administration of pirfeni done to amaximum of 1800 mg/day of pirfenidone, and reports a protocol forstepwise reduction and rechallenge with drug after an adverse event.

Abnormal liver function may manifest as abnormalities in levels ofbiomarkers of liver function, including alanine transaminase, aspartatetransaminase, bilirubin, and/or alkaline phosphatase, and may be anindicator of drug-induced liver injury. See FDA Draft Guidance forIndustry. Drug-Induced Liver Injury: Premarketing Clinical Evaluation,October 2007.

SUMMARY

One aspect of the invention provides methods for administering atherapeutically effective dose of pirfenidone to a patient that hasexhibited abnormal biomarkers of liver function after pirfenidoneadministration for the treatment of fibrosis, e.g. idiopathic pulmonaryfibrosis (IPF). In some embodiments, a patient is identified whoexhibits a significantly abnormal level of one, two, three or morebiomarkers of liver function, e.g. the level of a Grade 2 abnormality,after administration of an original full target dose of pirfenidone,e.g. about 2400 mg/day or 2403 mg/day. In such patients, the dose ofpirfenidone is reduced or discontinued until levels of the abnormalbiomarkers approach or are within normal range, after which patients areadministered increasing doses of pirfenidone, up to the original fulltarget dose. Alternatively, the dose of pirfenidone is not reduced atall, but liver biomarkers continue to be monitored. In anotherembodiment, after an optional temporary dose reduction ordiscontinuation, patients are administered pirfenidone at a permanentlyreduced dose of 1602 mg/day. As used herein, “original full target dose”means the therapeutically effective dose approved by the U.S. Food andDrug Administration or a similar agency in a foreign country, optionallyother than Japan. In some embodiments, the original full target dose isabout 2400 mg/day or 2403 mg/day pirfenidone, or about 34 mg/kg/day(e.g. 33-35 mg/kg/day), or from 2200 to 2600 mg/day pirfenidone, or from31 mg/kg/day to 37 mg/kg/day. The total daily dose is administered one,two or three times per day.

Thus, the invention provides methods of administering pirfenidone to apatient at doses of 2400 mg/day or 2403 mg/day after identifying thatthe patient has exhibited a liver function Grade 2 abnormality afterpirfenidone administration. In some embodiments, the methods involvecontinuing the full target dose, e.g. of 2400 mg/day or 2403 mg/day,without temporarily discontinuing or reducing the dose. The patient'sbiomarkers of liver function may continue to be monitored. In someembodiments, the method involves (a) administering a dose lower than2400 mg/day for a time period, e.g., one week, two weeks, three weeks,four weeks, one month, six weeks, or two months, followed by (b)administering a dose of 2400 mg/day or 2403 mg/day. In specificembodiments, the pirfenidone is temporarily discontinued before step(a).

In some embodiments of the methods, pirfenidone is administered to apatient exhibiting a liver function Grade 2 abnormality as follows: (a)administering about 1600 mg/day or 1602 mg/day pirfenidone for about oneweek, or until the liver function biomarkers return to Grade 0 or Grade1, and (b) administering the original full target dose for at least oneweek, two weeks, three weeks, four weeks or a month, two months, orthree months, or one year, or two years, or three years, or four years,or five years, or seven years, or ten years. Preferably, the total dailydose is administered three times per day, with food.

In some embodiments of the methods, pirfenidone is administered to apatient exhibiting a liver function Grade 2 abnormality as follows: (a)administering about 800 mg/day or 801 mg/day pirfenidone for about oneweek, or until the liver function biomarkers return to Grade 0 or Grade1, (b) administering about 1600 mg/day or 1602 mg/day pirfenidone forabout one week, and (c) administering the original full target dose fora time period of at least one week, two weeks, three weeks, four weeksor a month, two months, or three months, or one year, or two years, orthree years, or four years, or five years, or seven years, or ten years.Preferably, the total daily dose is administered three times per day,with food.

In some embodiments of the methods, pirfenidone is administered to apatient exhibiting a liver function Grade 2 abnormality as follows: (a)discontinuing pirfenidone for about one week, or until the liverfunction biomarkers return to Grade 0 or Grade 1, (b) administeringabout 800 mg/day or 801 mg/day pirfenidone for about one week, (c)administering about 1600 mg/day or 1602 mg/day pirfenidone for about oneweek, and (d) administering the original full target dose for a timeperiod of at least one week, two weeks, three weeks, four weeks or amonth, two months, or three months, or one year, or two years, or threeyears, or four years, or five years, or seven years, or ten years.Preferably, the total daily dose is administered three times per day,with food.

Alternatively, pirfenidone is administered to a patient exhibiting aliver function Grade 2 abnormality at a permanently reduced dose, e.g.800 or 801 mg/day, or 1600 or 1602 mg/day. In some embodiments,pirfenidone is administered to a patient exhibiting a liver functionGrade 2 abnormality as follows: administering about 1600 mg/day or 1602mg/day pirfenidone for a time period of at least one week, two weeks,three weeks, four weeks or a month, two months, or three months, or oneyear, or two years, or three years, or four years, or five years, orseven years, or ten years. In some embodiments, pirfenidone isadministered to a patient exhibiting a liver function Grade 2abnormality as follows: (a) administering about 800 mg/day or 801 mg/daypirfenidone for about a week, or until biomarkers of liver function arewithin normal limits, and (b) administering about 1600 mg/day or 1602mg/day pirfenidone to the patient for a time period of at least oneweek, two weeks, three weeks, four weeks or a month, two months, orthree months, or one year, or two years, or three years, or four years,or five years, or seven years, or ten years.

In other embodiments, pirfenidone is administered to a patientexhibiting a liver function Grade 2 abnormality as follows: (a)discontinuing pirfenidone for about one week, or until the liverfunction biomarkers return to Grade 0 or Grade 1, (b) administeringabout 800 mg/day or 801 mg/day pirfenidone for about a week, or untilbiomarkers of liver function are within normal limits, and (c)administering about 1600 mg/day or 1602 mg/day pirfenidone to thepatient for a time period of at least one week, two weeks, three weeks,four weeks or a month, two months, or three months, or one year, or twoyears, or three years, or four years, or five years, or seven years, orten years. In still other embodiments, pirfenidone is administered to apatient exhibiting a liver function Grade 2 abnormality as follows: (a)discontinuing pirfenidone for about one week, or until the liverfunction biomarkers return to Grade 0 or Grade 1, and (b) administeringabout 1600 mg/day or 1602 mg/day pirfenidone to the patient for a timeperiod of at least one week, two weeks, three weeks, four weeks or amonth, two months, or three months, or one year, or two years, or threeyears, or four years, or five years, or seven years, or ten years.

The invention also provides methods of administering pirfenidone to apatient at doses of 2400 mg/day or 2403 mg/day after identifying thatthe patient has exhibited a liver function Grade 1 abnormality afterpirfenidone administration. In some embodiments, the methods involvecontinuing the full target dose, e.g. of 2400 mg/day or 2403 mg/day,without temporarily discontinuing or reducing the dose. The patient'sbiomarkers of liver function may continue to be monitored. In someembodiments, the method involves (a) administering a dose lower than2400 mg/day for a time period, e.g., one week, two weeks, three weeks,four weeks, one month, six weeks, or two months, followed by (b)administering a dose of 2400 mg/day or 2403 mg/day. In specificembodiments, the pirfenidone is temporarily discontinued before step(a).

In some embodiments of the methods, pirfenidone is administered to apatient exhibiting a liver function Grade 1 abnormality as follows: (a)administering about 1600 mg/day or 1602 mg/day pirfenidone for a timeperiod, optionally about one week, or until the liver functionbiomarkers return to Grade 0, and (b) administering the original fulltarget dose for at least one week, two weeks, three weeks, four weeks ora month, two months, or three months, or one year, or two years, orthree years, or four years, or five years, or seven years, or ten years.Preferably, the total daily dose is administered three times per day,with food.

In some embodiments of the methods, pirfenidone is administered to apatient exhibiting a liver function Grade 1 abnormality as follows: (a)administering about 800 mg/day or 801 mg/day pirfenidone for a timeperiod, optionally about one week, or until the liver functionbiomarkers return to Grade 0, (b) administering about 1600 mg/day or1602 mg/day pirfenidone for a time period, optionally about one week,and (c) administering the original full target dose for a time period ofat least one week, two weeks, three weeks, four weeks or a month, twomonths, or three months, or one year, or two years, or three years, orfour years, or five years, or seven years, or ten years. Preferably, thetotal daily dose is administered three times per day, with food.

In some embodiments of the methods, pirfenidone is administered to apatient exhibiting a liver function Grade 1 abnormality as follows: (a)discontinuing pirfenidone for a time period, optionally about one week,or until the liver function biomarkers return to Grade 0, (b)administering about 800 mg/day or 801 mg/day pirfenidone for a timeperiod, optionally about one week, (c) administering about 1600 mg/dayor 1602 mg/day pirfenidone for a time period, optionally about one week,and (d) administering the original full target dose for a time period ofat least one week, two weeks, three weeks, four weeks or a month, twomonths, or three months, or one year, or two years, or three years, orfour years, or five years, or seven years, or ten years. Preferably, thetotal daily dose is administered three times per day, with food.

Alternatively, pirfenidone is administered at a permanently reduceddose, e.g. 800 or 801 mg/day, or 1600 or 1602 mg/day. In someembodiments, pirfenidone is administered to a patient exhibiting a liverfunction Grade 1 abnormality as follows: administering about 1600 mg/dayor 1602 mg/day pirfenidone for a time period of at least one week, twoweeks, three weeks, four weeks or a month, two months, or three months,or one year, or two years, or three years, or four years, or five years,or seven years, or ten years. In some embodiments, pirfenidone isadministered to a patient exhibiting a liver function Grade 1abnormality as follows: (a) administering about 800 mg/day or 801 mg/daypirfenidone for a time period, optionally about a week, or untilbiomarkers of liver function are within normal limits, and (b)administering about 1600 mg/day or 1602 mg/day pirfenidone to thepatient for a time period of at least one week, two weeks, three weeks,four weeks or a month, two months, or three months, or one year, or twoyears, or three years, or four years, or five years, or seven years, orten years.

In other embodiments, pirfenidone is administered to a patientexhibiting a liver function Grade 1 abnormality as follows: (a)discontinuing pirfenidone for a time period, optionally about one week,or until the liver function biomarkers return to Grade 0, (b)administering about 800 mg/day or 801 mg/day pirfenidone for about aweek, or until biomarkers of liver function are within normal limits,and (c) administering about 1600 mg/day or 1602 mg/day pirfenidone tothe patient for a time period of at least one week, two weeks, threeweeks, four weeks or a month, two months, or three months, or one year,or two years, or three years, or four years, or five years, or sevenyears, or ten years. In still other embodiments, pirfenidone isadministered to a patient exhibiting a liver function Grade 1abnormality as follows: (a) discontinuing pirfenidone for a time period,optionally about one week, or until the liver function biomarkers returnto Grade 0, and (b) administering about 1600 mg/day or 1602 mg/daypirfenidone to the patient for a time period of at least one week, twoweeks, three weeks, four weeks or a month, two months, or three months,or one year, or two years, or three years, or four years, or five years,or seven years, or ten years.

In any of the embodiments described herein, any of the reduced doses ofpirfenidone may be administered for a time period of 2 days, 3 days, 4days, 5 days, 6 days, one week, about two weeks, or until the level ofat least one biomarker of liver function has returned to within normallimits, or until all biomarkers or liver function has returned to withinnormal limits.

In any of the embodiments described herein, the patient can havefibrotic lesional tissue. Such a patient is a patient who would benefitfrom pirfenidone administration. In one embodiment, the patient issuffering from pulmonary fibrosis, idiopathic interstitial pneumonia,autoimmune lung diseases, benign prostate hypertrophy, coronary ormyocardial infarction, atrial fibrillation, cerebral infarction,myocardiac fibrosis, musculoskeletal fibrosis, post-surgical adhesions,liver cirrhosis, renal fibrotic disease, fibrotic vascular disease,scleroderma, Hermansky-Pudlak syndrome, neurofibromatosis, Alzheimer'sdisease, diabetic retinopathy, and/or skin lesions. In one embodiment,the patient is suffering from lymph node fibrosis associated with HIV.In one embodiment, the patient is suffering from pulmonary fibrosis, oridiopathic pulmonary fibrosis. In another embodiment, the patient is aperson who would benefit from pirfenidone administration, optionallywith the proviso that the patient is not suffering from idiopathicpulmonary fibrosis.

In some embodiments, the biomarker of liver function is alaninetransaminase, aspartate transaminase, bilirubin, and/or alkalinephosphatase. Elevated gamma-glutamyl transferase has been observed insome patients receiving pirfenidone, without clinical liver impairment,and thus elevated gamma-glutamyl transferase alone is not necessarily asign of liver impairment. In any of the embodiments described herein,biomarkers of liver function can exclude gamma-glutamyl transferase. Inanother embodiment, the abnormal level of alanine transaminase,aspartate transaminase, or alkaline phosphatase is greater than about2.5-fold increased compared to the upper limit of normal (ULN). In arelated embodiment, the abnormal level of alanine transaminase,aspartate transaminase, or alkaline phosphatase is greater than about2.5- to about 5-fold increased compared to the upper limit of normal(ULN), i.e. a “liver function Grade 2 abnormality”. In some embodiments,the abnormal level of bilirubin is greater than about 1.5- to about3-fold increased compared to the upper limit of normal (ULN), i.e., a“liver function Grade 2 abnormality”.

In some embodiments the abnormal biomarkers of liver function, e.g.elevated alanine transaminase and/or aspartate transaminase and/orelevated bilirubin, are accompanied by clinical signs of impaired liverfunction such as jaundice.

Further aspects and advantages will be apparent to those of ordinaryskill in the art from a review of the following detailed description,taken in conjunction with the examples. While the method is susceptibleof embodiments in various forms, the description hereafter includesspecific embodiments with the understanding that the disclosure isillustrative, and is not intended to limit the invention to the specificembodiments described herein.

DETAILED DESCRIPTION

The invention provides methods for administering a full therapeuticallyeffective dose of pirfenidone to a patient that has exhibited abnormallevels of biomarkers of liver function after the patient has beentreated with pirfenidone. Because liver function abnormalities can beindicative of drug-induced liver injury (hepatotoxicity), it isimportant to determine whether the abnormalities reflect liver injury ormerely indicate limited toxicity that will resolve over time whilecontinuing to take the drug. According to the present invention, evenpatients that exhibit abnormal liver function may continue takingpirfenidone at the original full target dose, optionally after a shorttime period of discontinuing pirfenidone or taking the pirfenidone atreduced doses. This administration regimen has the advantage ofmaximizing the time on the full target dose of drug and therefore thepotential for a beneficial therapeutic effect.

The patient may be suffering from any disease for which pirfenidonetherapy may be useful in ameliorating symptoms. Such a patient is apatient who would benefit from pirfenidone administration. Thesediseases include, but are not limited to: chronic obstructive pulmonarydisease (COPD), inflammatory pulmonary fibrosis (IPF), rheumatoidarthritis; rheumatoid spondylitis; osteoarthritis; gout, other arthriticconditions; sepsis; septic shock; endotoxic shock; gram-negative sepsis;toxic shock syndrome; myofacial pain syndrome (MPS); Shigellosis;asthma; adult respiratory distress syndrome; inflammatory bowel disease;Crohn's disease; psoriasis; eczema; ulcerative colitis; glomerularnephritis; scleroderma; chronic thyroiditis; Grave's disease; Ormond'sdisease; autoimmune gastritis; myasthenia gravis; autoimmune hemolyticanemia; autoimmune neutropenia; thrombocytopenia; pancreatic fibrosis;chronic active hepatitis including hepatic fibrosis; acute and chronicrenal disease; renal fibrosis, irritable bowel syndrome; pyresis;restenosis; cerebral malaria; stroke and ischemic injury; neural trauma;Alzheimer's disease; Huntington's disease; Parkinson's disease; acuteand chronic pain; allergies, including allergic rhinitis and allergicconjunctivitis; cardiac hypertrophy, chronic heart failure; acutecoronary syndrome; cachexia; malaria; leprosy; leishmaniasis; Lymedisease; Reiter's syndrome; acute synoviitis; muscle degeneration,bursitis; tendonitis; tenosynoviitis; herniated, ruptured, or prolapsedintervertebral disk syndrome; osteopetrosis; thrombosis; silicosis;pulmonary sarcosis; bone resorption diseases, such as osteoporosis ormultiple myeloma-related bone disorders; cancer, including but notlimited to metastatic breast carcinoma, colorectal carcinoma, malignantmelanoma, gastric cancer, and non-small cell lung cancer;graft-versus-host reaction; and auto-immune diseases, such as MultipleSclerosis, lupus and fibromyalgia; AIDS and other viral diseases such asHerpes Zoster, Herpes Simplex I or II, influenza virus, Severe AcuteRespiratory Syndrome (SARS) and cytomegalovirus; and diabetes mellitus.In addition, the methods of the embodiments can be used to treatproliferative disorders (including both benign and malignanthyperplasias), including acute myelogenous leukemia, chronic myelogenousleukemia, Kaposi's sarcoma, metastatic melanoma, multiple myeloma,breast cancer, including metastatic breast carcinoma; colorectal.carcinoma; malignant melanoma; gastric cancer; non-small cell lungcancer (NSCLC); bone metastases, and the like; pain disorders includingneuromuscular pain, headache, cancer pain, dental pain, and arthritispain; angiogenic disorders including solid tumor angiogenesis, ocularneovascularization, and infantile hemangioma; conditions associated withthe cyclooxygenase and lipoxygenase signaling pathways, includingconditions associated with prostaglandin endoperoxide synthase-2(including edema, fever, analgesia, and pain); organ hypoxia;thrombin-induced platelet aggregation; protozoal diseases.

The methods of the invention optionally include identifying abnormalliver function in a patient receiving pirfenidone, and monitoringbiomarkers of liver function in a patient receiving a reduced dose ofpirfenidone. In any of the methods described herein, AST and/or ALT maybe elevated, e.g. to a Grade 2 or Grade 3 level. In some embodiments,the elevation is to a Grade 1 level. Alternatively, AST and bilirubinmay be elevated, or AST or ALP may be elevated, or AST and GGT may beelevated, or ALT and bilirubin may be elevated, or ALT and ALP may beelevated, or ALT and GGT may be elevated, or bilirubin and ALP may beelevated, or bilirubin and GGT may be elevated, e.g., to a Grade 1,Grade 2, or Grade 3 level. Alternatively, three biomarkers of liverfunction may be elevated, e.g., ALT and AST and bilirubin, or ALT andAST and ALP, to a Grade 1, Grade 2, or Grade 3 level. In any of theembodiments described herein, biomarkers of liver function can excludegamma-glutamyl transferase.

In some embodiments of the methods, pirfenidone is administered to apatient exhibiting a liver function Grade 2 abnormality afterpirfenidone administration as follows: (a) administering at least about1600 mg/day or 1602 mg/day pirfenidone, or about 23 mg/kg/day (e.g.22-24 mg/kg/day), or from 1400-1800 mg/day pirfenidone, or from 20mg/kg/day to 26 mg/kg/day, for a time period. In some embodiments, step(a) is followed by (b) administering the original full target dose. Inother embodiments, the original full target dose is continued without atemporary reduction or discontinuation of the dose. In some embodiments,the time period of step (a) is 2 days, 3 days, 4 days, 5 days, 6 days,about one week, about two weeks, about three weeks, about four weeks,about 1 month, or until the level of at least one biomarker of liverfunction has returned to within normal limits, or until all biomarkersor liver function has returned to within normal limits. In someembodiments, step (b) is carried out for a time period of at least oneweek, two weeks, three weeks, four weeks or a month, two months, orthree months, or one year, or two years, or three years, or four years,or five years, or seven years, or ten years, or more. Optionally themethod includes measuring one or more biomarkers of liver functionduring step (a) and/or step (b).

In some embodiments of the methods, pirfenidone is administered to apatient exhibiting a liver function Grade 2 abnormality as follows: (a)administering at least about 800 mg/day or 801 mg/day pirfenidone, orabout 11 mg/kg/day (e.g. 10-12 mg/kg/day), or from 600-1000 mg/day, orfrom 700-900 mg/day, or from 8 mg/kg/day to 15 mg/kg/day, for a timeperiod, (b) administering at least about 1600 mg/day or 1602 mg/daypirfenidone, or about 23 mg/kg/day (e.g. 22-24 mg/kg/day), or from1400-1800 mg/day pirfenidone, or from 20 mg/kg/day to 26 mg/kg/day, fora time period, and (c) administering the original full target dose. Insome embodiments, the time period of step (a) is 2 days, 3 days, 4 days,5 days, 6 days, about one week, about two weeks, about three weeks,about four weeks, about 1 month, or until the level of at least onebiomarker of liver function has returned to within normal limits, or toGrade 1, or until all biomarkers or liver function has returned towithin normal limits, or to Grade 1. In some embodiments, the timeperiod of step (b) is 2 days, 3 days, 4 days, 5 days, 6 days, about oneweek, about two weeks, about three weeks, about four weeks, about 1month, or until the level of at least one biomarker of liver functionhas returned to within normal limits, or to Grade 1, or until allbiomarkers or liver function has returned to within normal limits, or toGrade 1. In some embodiments, step (c) is carried out for a time periodof at least one week, two weeks, three weeks, four weeks or a month, twomonths, or three months, or one year, or two years, or three years, orfour years, or five years, or seven years, or ten years, or more.Optionally the method includes measuring one or more biomarkers of liverfunction during step (a) and/or step (b) and/or step (c).

In some embodiments of the methods, pirfenidone is administered to apatient exhibiting a liver function Grade 2 abnormality as follows: (a)discontinuing pirfenidone for a time period, (b) administering at leastabout 800 mg/day or 801 mg/day pirfenidone, or about 11 mg/kg/day (e.g.10-12 mg/kg/day), or from 600-1000 mg/day, or from 700-900 mg/day, orfrom 8 mg/kg/day to 15 mg/kg/day, for a time period, (c) administeringat least about 1600 mg/day or 1602 mg/day pirfenidone, or about 23mg/kg/day (e.g. 22-24 mg/kg/day), or from 1400-1800 mg/day pirfenidone,or from 20 mg/kg/day to 26 mg/kg/day, for a time period, and (d)administering the original full target dose. In some embodiments, thetime period of step (a) is 2 days, 3 days, 4 days, 5 days, 6 days, aboutone week, about two weeks, about three weeks, about four weeks, about 1month, or until the level of at least one biomarker of liver functionhas returned to within normal limits, or to Grade 1, or until allbiomarkers or liver function has returned to within normal limits, or toGrade 1. In some embodiments, the time period of step (b) is 2 days, 3days, 4 days, 5 days, 6 days, about one week, about two weeks, aboutthree weeks, about four weeks, about 1 month, or until the level of atleast one biomarker of liver function has returned to within normallimits, or to Grade 1, or until all biomarkers or liver function hasreturned to within normal limits, or to Grade 1. In some embodiments,the time period of step (c) is 2 days, 3 days, 4 days, 5 days, 6 days,about one week, about two weeks, about three weeks, about four weeks,about 1 month, or until the level of at least one biomarker of liverfunction has returned to within normal limits, or to Grade 1, or untilall biomarkers or liver function has returned to within normal limits,or to Grade 1. In some embodiments, step (d) is carried out for a timeperiod of at least one week, two weeks, three weeks, four weeks or amonth, two months, or three months, or one year, or two years, or threeyears, or four years, or five years, or seven years, or ten years, ormore. Optionally the method includes measuring one or more biomarkers ofliver function during step (a) and/or step (b) and/or step (c) and/orstep (d).

In some embodiments of the methods, pirfenidone is administered to apatient exhibiting a liver function Grade 1 abnormality as follows: (a)administering at least about 1600 mg/day or 1602 mg/day pirfenidone, orabout 23 mg/kg/day (e.g. 22-24 mg/kg/day), or from 1400-1800 mg/daypirfenidone, or from 20 mg/kg/day to 26 mg/kg/day, for a time period,and (b) administering the original full target dose. In someembodiments, the time period of step (a) is 2 days, 3 days, 4 days, 5days, 6 days, about one week, about two weeks, about three weeks, aboutfour weeks, about 1 month, or until the level of at least one biomarkerof liver function has returned to within normal limits, or until allbiomarkers or liver function has returned to within normal limits. Insome embodiments, step (b) is carried out for a time period of at leastone week, two weeks, three weeks, four weeks or a month, two months, orthree months, or one year, or two years, or three years, or four years,or five years, or seven years, or ten years, or more. Optionally themethod includes measuring one or more biomarkers of liver functionduring step (a) and/or step (b).

In some embodiments of the methods, pirfenidone is administered to apatient exhibiting a liver function Grade 1 abnormality as follows: (a)administering at least about 800 mg/day or 801 mg/day pirfenidone, orabout 11 mg/kg/day (e.g. 10-12 mg/kg/day), or from 600-1000 mg/day, orfrom 700-900 mg/day, or from 8 mg/kg/day to 15 mg/kg/day, for a timeperiod, (b) administering at least about 1600 mg/day or 1602 mg/daypirfenidone, or about 23 mg/kg/day (e.g. 22-24 mg/kg/day), or from1400-1800 mg/day pirfenidone, or from 20 mg/kg/day to 26 mg/kg/day, fora time period, and (c) administering the original full target dose. Insome embodiments, the time period of step (a) is 2 days, 3 days, 4 days,5 days, 6 days, about one week, about two weeks, about three weeks,about four weeks, about 1 month, or until the level of at least onebiomarker of liver function has returned to within normal limits, or toGrade 1, or until all biomarkers or liver function has returned towithin normal limits, or to Grade 1. In some embodiments, the timeperiod of step (b) is 2 days, 3 days, 4 days, 5 days, 6 days, about oneweek, about two weeks, about three weeks, about four weeks, about 1month, or until the level of at least one biomarker of liver functionhas returned to within normal limits, or to Grade 1, or until allbiomarkers or liver function has returned to within normal limits, or toGrade 1. In some embodiments, step (c) is carried out for a time periodof at least one week, two weeks, three weeks, four weeks or a month, twomonths, or three months, or one year, or two years, or three years, orfour years, or five years, or seven years, or ten years, or more.Optionally the method includes measuring one or more biomarkers of liverfunction during step (a) and/or step (b) and/or step (c).

In some embodiments of the methods, pirfenidone is administered to apatient exhibiting a liver function Grade 1 abnormality as follows: (a)discontinuing pirfenidone for a time period, (b) administering at leastabout 800 mg/day or 801 mg/day pirfenidone, or about 11 mg/kg/day (e.g.10-12 mg/kg/day), or from 600-1000 mg/day, or from 700-900 mg/day, orfrom 8 mg/kg/day to 15 mg/kg/day, for a time period, (c) administeringat least about 1600 mg/day or 1602 mg/day pirfenidone, or about 23mg/kg/day (e.g. 22-24 mg/kg/day), or from 1400-1800 mg/day pirfenidone,or from 20 mg/kg/day to 26 mg/kg/day, for a time period, and (d)administering the original full target dose. In some embodiments, thetime period of step (a) is 2 days, 3 days, 4 days, 5 days, 6 days, aboutone week, about two weeks, about three weeks, about four weeks, about 1month, or until the level of at least one biomarker of liver functionhas returned to within normal limits, or to Grade 1, or until allbiomarkers or liver function has returned to within normal limits, or toGrade 1. In some embodiments, the time period of step (b) is 2 days, 3days, 4 days, 5 days, 6 days, about one week, about two weeks, aboutthree weeks, about four weeks, about 1 month, or until the level of atleast one biomarker of liver function has returned to within normallimits, or to Grade 1, or until all biomarkers or liver function hasreturned to within normal limits, or to Grade 1. In some embodiments,the time period of step (c) is 2 days, 3 days, 4 days, 5 days, 6 days,about one week, about two weeks, about three weeks, about four weeks,about 1 month, or until the level of at least one biomarker of liverfunction has returned to within normal limits, or to Grade 1, or untilall biomarkers or liver function has returned to within normal limits,or to Grade 1. In some embodiments, step (d) is carried out for a timeperiod of at least one week, two weeks, three weeks, four weeks or amonth, two months, or three months, or one year, or two years, or threeyears, or four years, or five years, or seven years, or ten years, ormore. Optionally the method includes measuring one or more biomarkers ofliver function during step (a) and/or step (b) and/or step (c) and/orstep (d).

Pirfenidone can be provided in tablet or capsule forms or any other oraldosage form, and typically is formulated for oral administration.Exemplary capsule formulations are described in WO 2007/038315 (Int'lAppl. No. PCT/US2006/037057).

Pirfenidone therapy can be associated with adverse effects includingphotosensitivity rash, anorexia (decreased appetite), stomachdiscomfort, nausea, heartburn, drowsiness (somnolence), fatigue, upperrespiratory tract infection, fever, positive urinary occult blood,elevation of C-reactive protein (CRP), decreased weight, headache,constipation, and malaise. Abnormal liver function also can occur as anadverse effect (AE) in patients receiving pirfenidone. Prior toreceiving pirfenidone, the baseline liver function of the patient canbe, and typically is, normal. Liver function can be assessed by variousmeans known in the art, such as blood chemistry tests measuringbiomarkers of liver function. Examples of biomarkers of liver functioninclude, but are not limited to, alanine transaminase (ALT), aspartatetransaminase (AST), bilirubin, alkaline phosphatase (ALP), andgamma-glutamyl transferase (GGT).

Alanine transaminase (ALT), also called serum glutamic pyruvatetransaminase (SGPT) or alanine aminotransferase (ALAT), catalyzes thetransfer of an amino group from alanine to α-ketoglutarate to producepyruvate and glutamate. When the liver is damaged, levels of ALT in theblood can rise due to the leaking of ALT into the blood from damaged ornecrosed hepatocytes.

Aspartate transaminase (AST) also called serum glutamic oxaloacetictransaminase (SGOT or GOT) or aspartate aminotransferase (ASAT),catalyzes the transfer of an amino group from aspartate toα-ketoglutarate to produce oxaloacetate and glutamate. AST can increasein response to liver damage. Elevated AST also can result from damage toother sources, including red blood cells, cardiac muscle, skeletalmuscle, kidney tissue, and brain tissue. The ratio of AST to ALT can beused as a biomarker of liver damage.

Bilirubin is a catabolite of heme that is cleared from the body by theliver. Conjugation of bilirubin to glucuronic acid by hepatocytesproduces direct bilirubin, a water-soluble product that is readilycleared from the body. Indirect bilirubin is unconjugated, and the sumof direct and indirect bilirubin constitutes total bilirubin. Elevatedtotal bilirubin can be indicative of liver impairment.

Alkaline phosphatase (ALP) hydrolyzes phosphate groups from variousmolecules and is present in the cells lining the biliary ducts of theliver. ALP levels in plasma can rise in response to liver damage, andare higher in growing children and elderly patients with Paget'sdisease. However, elevated ALP levels usually reflect biliary treedisease.

Adverse effect Grades for abnormal liver function are defined herein bythe modified Common Toxicity Criteria (CTC) provided in Table 1. See theCommon Terminology Criteria for Adverse Events v3.0 (CTCAE) publishedAug. 9, 2006 by the National Cancer Institute, incorporated herein byreference in its entirety.

TABLE 1 Modified Common Toxicity Criteria Grade Toxicity 0 1 2 3 4 ALTWNL >ULN-2.5 × ULN >2.5-5 × ULN >5-20 × ULN >20 × ULN AST WNL >ULN-2.5 ×ULN >2.5-5 × ULN >5-20 × ULN >20 × ULN Bilirubin WNL >ULN-1.5 ×ULN >1.5-3 × ULN >3-10 × ULN >10 × ULN ALP WNL >ULN-2.5 × ULN >2.5-5 ×ULN >5-20 × ULN >20 × ULN GGT WNL >ULN-2.5 × ULN >2.5-5 × ULN >5-20 ×ULN >20 × ULN (WNL = within normal limits; ULN = upper limit of normal)

The ULN for various indicators of liver function depends on the assayused, the patient population, and each laboratory's normal range ofvalues for the specified biomarker, but can readily be determined by theskilled practitioner. Exemplary values for normal ranges for a healthyadult population are set forth in Table 2 below. See Cecil Textbook ofMedicine, pp. 2317-2341, W.B. Saunders & Co. (1985).

TABLE 2 ALT 8-20 U/L AST 8-20 U/L Bilirubin 0.2-1.0 mg/dL 3.4-17.1μmol/L ALP 20-70 U/L GGT Men: 9-50 U/L Women: 8-40 U/L

Grade 0 levels are characterized by biomarker levels within normallimits (WNL). “Normal” liver function, as used herein, refers to Grade 0adverse effects. “Abnormal” liver function, as used herein, refers toGrade 1 and above adverse effects.

“Grade 1 liver function abnormalities” include elevations in ALT, AST,ALP, or GGT greater than the ULN and less than or equal to 2.5-times theULN. Grade 1 liver function abnormalities also include elevations ofbilirubin levels greater than the ULN and less than or equal to1.5-times the ULN.

“Grade 2 liver function abnormalities” include elevations in alaninetransaminase (ALT), aspartate transaminase (AST), alkaline phosphatase(ALP), or gamma-glutamyl transferase (GGT) greater than 2.5-times andless than or equal to 5-times the upper limit of normal (ULN). Grade 2liver function abnormalities also include elevations of bilirubin levelsgreater than 1.5-times and less than or equal to 3-times the ULN.

“Grade 3 liver function abnormalities” include elevations in ALT, AST,ALP, or GGT greater than 5-times and less than or equal to 20-times theULN. Grade 3 liver function abnormalities also include elevations ofbilirubin levels greater than 3-times and less than or equal to 10-timesthe ULN.

“Grade 4 liver function abnormalities” include elevations in ALT, AST,ALP, or GGT greater than 20-times the ULN. Grade 4 liver functionabnormalities also include elevations of bilirubin levels greater than10 the ULN.

The present disclosure provides methods for treating a patient havingidiopathic pulmonary fibrosis and receiving a full target dose ofpirfenidone, wherein the full target dose is 2400 or 2403 mg pirfenidoneper day. In accordance with the methods, a patient with abnormal liverfunction is administered a second dose of pirfenidone, wherein thesecond dose is 1600 or 1602 mg pirfenidone per day until liver functionis within normal limits, followed by administering the patient the fulltarget dose of 2400 or 2403 mg pirfenidone per day.

The present disclosure also provides methods for treatment of patientsthat exhibit Grade 1 abnormality in one or more biomarkers of liverfunction after pirfenidone administration. The method includesadministering to the patient pirfenidone at doses of 2400 mg/day or 2403mg/day or administering to the patient pirfenidone at doses of 1600mg/day or 1602 mg/day. Preferably, the patient may be receivingpirfenidone for treatment of idiopathic pulmonary fibrosis.Alternatively, the patient may be suffering from a condition for whichpirfenidone administration may be beneficial. Optionally, patients mayreceive reduced doses or discontinue treatment for a time period, andthen resume administration of pirfenidone.

The methods disclosed herein are contemplated to include embodimentsincluding any combination of one or more of the additional optionalelements, features, and steps further described herein (including thosedescribed in the examples), unless stated otherwise.

Ranges may be expressed herein as from “about” or “approximately” oneparticular value and/or to “about” or “approximately” another particularvalue. When such a range is expressed, another embodiment includes fromthe one particular value and/or to the other particular value.Similarly, when values are expressed as approximations, by use of theantecedent “about,” it will be understood that the particular valueforms another embodiment.

It will be appreciated that the invention provides pirfenidone as amedicament wherein the administration pattern of the medicamentcomprises administering according to any of the treatment methodsdescribed herein.

It will be appreciated that the invention provides pirfenidone for usein treating a patient with idiopathic pulmonary fibrosis or a patientwho would benefit from pirfenidone administration according to any ofthe treatment regimes as described above with respect to the methods ofthe invention for administering pirfenidone to a patient for treatingidiopathic pulmonary fibrosis or to a patient who would benefit frompirfenidone administration. Pirfenidone is packaged and presented foruse in a treating a patient with idiopathic pulmonary fibrosis or apatient who would benefit from pirfenidone administration according tosuch treatment regimes. Pirfenidone is administered to the patient inaccordance with the treatment regimes as described above. The patient isone who has exhibited abnormal biomarkers of liver function afterpirfenidone administration as is described above with respect to themethods of the invention for administering pirfenidone to a patient fortreating idiopathic pulmonary fibrosis or to a patient who would benefitfrom pirfenidone administration.

In particular, the invention includes pirfenidone for use in treating apatient with idiopathic pulmonary fibrosis or a patient who wouldbenefit from pirfenidone administration, said patient having exhibited aGrade 1 or Grade 2 abnormality in one or more biomarkers of liverfunction after pirfenidone administration, wherein said patient isadministered pirfenidone at doses of 2400 mg/day or 2403 mg/day.Optionally, prior to administration of pirfenidone at doses of 2400mg/day or 2403 mg/day, said patient is administered pirfenidone at doseslower than 2400 mg/day for a time period.

It will be appreciated that the invention provides the use ofpirfenidone in the manufacture of a medicament for treating a patientwith idiopathic pulmonary fibrosis or a patient who would benefit frompirfenidone administration according to any of the treatment regimes asdescribed above with respect to any of the methods. The medicamentsmanufactured according to this aspect of the invention are for use intreating a patient with idiopathic pulmonary fibrosis or a patient whowould benefit from pirfenidone administration in accordance with suchtreatment regimes. The medicament so manufactured is administered to thepatient in accordance with the treatment regimes as described above. Thepatient is one who has exhibited abnormal biomarkers of liver functionafter pirfenidone administration as is described above with respect tothe methods of the invention for administering pirfenidone to a patientfor treating idiopathic pulmonary fibrosis or a patient who wouldbenefit from pirfenidone administration.

In particular, the invention includes the use of pirfenidone in themanufacture of a medicament for treating a patient with idiopathicpulmonary fibrosis or a patient who would benefit from pirfenidoneadministration, said patient having exhibited a Grade 1 or Grade 2abnormality in one or more biomarkers of liver function afterpirfenidone administration, wherein said patient is administeredpirfenidone at doses of 2400 mg/day or 2403 mg/day. Optionally, prior toadministration of pirfenidone at doses of 2400 mg/day or 2403 mg/day,said patient is administered pirfenidone at doses lower than 2400 mg/dayfor a time period.

In respect of the aspects of the invention relating to pirfenidone foruse in treating a patient with idiopathic pulmonary fibrosis, and to useof pirfenidone in the manufacture of a medicament for treating a patientwith idiopathic pulmonary fibrosis, the preferences expressed withrespect to the preferred embodiments of the aspect of the inventionrelating to a method for administering pirfenidone to treat a patientwith idiopathic pulmonary fibrosis apply in the same way. Similarly, theexamples relate to pirfenidone for use in treating a patient withidiopathic pulmonary fibrosis, and to use of pirfenidone in themanufacture of a medicament for treating a patient with idiopathicpulmonary fibrosis, as well as to a method for administering pirfenidoneto a patient for treating idiopathic pulmonary fibrosis.

EXAMPLES

The following examples are provided for illustration and are notintended to limit the scope of the invention.

Example 1 Pirfenidone Dosing Regimen

Patients begin pirfenidone treatment by receiving escalating doses ofpirfenidone over a period of 15 days until the full maintenance dose isreached. Specifically, from days 1 to 7, patients are administered onecapsule of 267 mg pirfenidone three times per day. During days 8 to 14,patients receive two capsules of 267 mg pirfenidone three times per day.From day 15 onward, patients are treated with three capsules of 267 mgpirfenidone three times per day. Pirfenidone is administered orally, andeach dose should be taken with food. If the patient is unable to eat,then the pirfenidone dose should be taken with milk or juice (excludinggrapefruit juice).

Pirfenidone is known to cause photosensitivity reactions; therefore,throughout the treatment period, patients should use sun block thatprotects against at least UV-A with a sun protective factor (SPF) of 50.In addition, patients should wear appropriate clothing to minimize sunexposure, and if possible, avoid other medications known to cause photosensitivity reactions.

Once the full maintenance dose is reached, pirfenidone is administeredorally to patients three times per day to provide a daily dose of 2403mg pirfenidone. Each of the three doses of 801 mg pirfenidone includesthree capsules of 267 mg pirfenidone each. The contents of thepirfenidone 267 mg capsules are pirfenidone (82.15%); croscarmellosesodium (8.15%); microcrystalline cellulose (7.39%); povidine, USP, EP(1.85%); and magnesium stearate (0.46%).

Patients are treated with pirfenidone for up to 72 weeks. Some patientsare treated longer than 72 weeks. At weeks 2, 4, 6, 12, and every 12weeks (±2 weeks) thereafter during the treatment period, with theexception of week 72 and the treatment completion visit, patients areexamined and histories are collected as detailed in the steps below.

1. Patient history is collected to include review of adverse effects(AEs) and severe adverse effects (SAEs), use of concomitant medications,use of oxygen, hospitalizations, IPF exacerbations or acute respiratorydecompensation, and dosing.

2. Patients receive a physical examination, and vital signs and weightare measured.

3. Pulmonary function is assessed by spirometry before and afteradministration of bronchodilators. Forced vital capacity (FVC) andforced expiratory volume in 1 second (FEV1) are measured.

4. Clinical laboratory tests are performed, including hematology, serumchemistries, pregnancy tests for women of childbearing capacity, andurinalysis with microscopic examination.

5. Questionnaires are administered, including the University ofCalifornia at San Diego Shortness of Breath Questionnaire (UCSD SOBQ),St. George's Hospital Respiratory Questionnaire (SGRQ), and the WorldHealth Organization Quality of Life (WHO QOL) questionnaire. After week72, only the UCSD SOBQ and SGRQ are obtained at the scheduled 12 weekvisits.

Additionally, every 24 weeks starting with Week 12 (for example, weeks12, 36, and 60), electrocardiogram (ECG) measurements are obtained. ECGdata is obtained before administering bronchodilators for the pulmonaryfunction test (PFT) measurements. At the week 36 visit, pharmacokinetic(PK) data is obtained for selected patients.

If a patient experiences a Grade 1 or greater elevation in alaninetransaminase (ALT), aspartate transaminase (AST), or bilirubin atbaseline or after the start of pirfenidone dosing up to and includingweek 6, an additional safety chemistry blood test must be obtainedbetween weeks 8 and 10.

Example 2 Modification of Pirfenidone Dosing Regimen in Response toGrade 2 Liver Function Test (LFT) Elevations

Patients are treated with pirfenidone in accordance with Example 1.During the course of pirfenidone treatment, patients exhibiting abnormalliver function test results are candidates for dose modification. Asdescribed in Example 1, serum chemistry tests are performed at scheduledintervals during the treatment period to monitor various parameters,including biomarkers of liver function such as alanine transaminase(ALT), aspartate transaminase (AST), bilirubin, alkaline phosphatase(ALP), and gamma-glutamyl transferase (GGT).

If a patient experiences a Grade 2 increase in any one of AST, ALT orbilirubin, the pirfenidone dose is reduced to one capsule of 267 mgpirfenidone three times per day. While receiving the reduced pirfenidonedose, the patient undergoes additional monitoring of AST, ALT andbilirubin. The reduced pirfenidone dose is continued at least until AST,ALT and bilirubin are all Grade 1 or within normal limits (Grade 0). Thereduced pirfenidone dose can be administered for a period of time afterAST, ALT and bilirubin have reached Grade 1 or Grade 0.

At any time after AST, ALT and bilirubin have resolved to Grade 0 orGrade 1, the pirfenidone dose can be re-escalated in a manner consistentwith the initial dose escalation, up to a dose of 6 capsules per day.After AST, ALT and bilirubin have resolved to Grade 0 or Grade 1, thepirfenidone dose also can be re-escalated in a manner consistent withthe initial dose escalation, up to the maximum of 9 capsules per day.

Serum chemistry tests are optionally performed at scheduled intervalsduring the escalation period, e.g. weekly or every 2 weeks, or every 3weeks, or every month to monitor various parameters, includingbiomarkers of liver function such as alanine transaminase (ALT),aspartate transaminase (AST), bilirubin, alkaline phosphatase (ALP), andgamma-glutamyl transferase (GGT).

Example 3 Temporary Discontinuation of Pirfenidone Dosing in Response toGrade 2 Liver Function Test (LFT) Elevations

Patients are treated with pirfenidone in accordance with Example 1.During the course of pirfenidone treatment, patients exhibiting abnormalliver function test results are candidates for dose modification. Asdescribed in Example 1, serum chemistry tests are performed at scheduledintervals during the treatment period to monitor various parameters,including biomarkers of liver function such as alanine transaminase(ALT), aspartate transaminase (AST), bilirubin, alkaline phosphatase(ALP), and gamma-glutamyl transferase (GGT).

If a patient experiences a Grade 2 increase in any one of AST, ALT orbilirubin, the pirfenidone dose is discontinued. Followingdiscontinuation of the pirfenidone dose, the patient undergoesadditional monitoring of AST, ALT and bilirubin. Pirfenidone dosing isdiscontinued at least until AST, ALT and bilirubin are all Grade 1 orwithin normal limits (Grade 0). The pirfenidone dose can be discontinuedfor a period of time after AST, ALT and bilirubin have reached Grade 1or Grade 0.

After AST, ALT and bilirubin have resolved to Grade 0 or Grade 1, if thepatient has been off drug for 14 days or more, the pirfenidone dose isre-escalated in a manner consistent with the initial dose escalation, upto a dose of 6 or 9 capsules per day, i.e. 1602 mg/day or 2403 mg/day.Alternatively, after AST, ALT and bilirubin have resolved to Grade 0 orGrade 1, the pirfenidone dose is re-instituted at a dose of 6 capsulesper day, i.e. 1602 mg/day, and re-escalated after 1 week to the maximumof 9 capsules per day.

Serum chemistry tests are optionally performed at scheduled intervalsduring the escalation period, e.g. weekly, or every 2 weeks, or everymonth, to monitor various parameters, including biomarkers of liverfunction such as alanine transaminase (ALT), aspartate transaminase(AST), bilirubin, alkaline phosphatase (ALP), and gamma-glutamyltransferase (GGT).

Example 4 Modification of Pirfenidone Dosing Regimen to 2 Capsules ThreeTimes per Day in Response to Grade 2 Liver Function Test (LFT)Elevations

Patients are treated with pirfenidone in accordance with Example 1.During the course of pirfenidone treatment, patients exhibiting abnormalliver function test results are candidates for dose modification. Asdescribed in Example 1, serum chemistry tests are performed at scheduledintervals during the treatment period to monitor various parameters,including biomarkers of liver function such as alanine transaminase(ALT), aspartate transaminase (AST), bilirubin, alkaline phosphatase(ALP), and gamma-glutamyl transferase (GGT).

If a patient experiences a Grade 2 increase in any one of AST, ALT orbilirubin, the pirfenidone dose is reduced to two capsules of 267 mgpirfenidone three times per day, i.e. 1602 mg/day. While receiving thereduced pirfenidone dose, the patient undergoes additional monitoring ofAST, ALT and bilirubin. The reduced pirfenidone dose is continued atleast until AST, ALT and bilirubin are all Grade 1 or within normallimits (Grade 0). The reduced pirfenidone dose can be administered for aperiod of time after AST, ALT and bilirubin have reached Grade 1 orGrade 0.

After 1 week of treatment at 1602 mg/day, if AST, ALT and bilirubin haveresolved to Grade 0 or Grade 1, the pirfenidone dose can be re-escalatedto the maximum of 9 capsules per day, i.e. 2403 mg.

Example 5 No Modification of Pirfenidone Dosing Regime in Response to aGrade 1 or Grade 2 Liver Function Test (LFT) Elevations

Patients were treated with pirfenidone in accordance with Example 1.During the course of pirfenidone treatment, some patients exhibitedabnormal liver function test results. As described in Example 1, serumchemistry tests were performed at scheduled intervals during thetreatment period to monitor various parameters, including biomarkers ofliver function such as alanine transaminase (ALT), aspartatetransaminase (AST), bilirubin, alkaline phosphate (ALP), andgamma-glutamyl transferase (GGT).

If a patient exhibited a Grade 1 or Grade 2 increase in any one of AST,ALT, or bilirubin, the pirfenidone dose was not reduced for somepatients. The patient continued to receive the full target dose of 2403mg/day. While receiving the full target dose, the patient was monitoredfor AST, ALT, and bilirubin levels.

Example 6 Incidence of Liver Function Abnormality and Dosing RegimenResponse

Grade 1 Abnormalities in Liver Function

In a study of 345 patients with idiopathic pulmonary fibrosis receivingpirfenidone three times per day for a total daily dose of 2403 mg/day,49 patients without a baseline liver function abnormality exhibited aGrade 1 elevation in AST or ALT levels after pirfenidone administration.Of the 49 patients, three patients with a Grade 1 liver function testelevation had a treatment emergent adverse event of increased AST orALT. In one patient, study drug dose was reduced to 1602 mg/day for theremainder of study participation (from Day 51 to Day 602), and the Grade1 AST or ALT abnormality returned to Grade 0. For the second patient,study drug dose was reduced to 1602 mg/day and then increased to 2403mg/day for remainder of study participation, and ALT returned to Grade0. The third patient had study drug dose reduced to 801 mg/day,ultimately completing study at 1602 mg/day, at which time ALT returnedto Grade 0. The remaining patients (46 patients) received no dosemodification.

Grade 2 Abnormalities in Liver Function

Fifteen patients developed a Grade 2 liver function test abnormality inAST and/or ALT levels after pirfenidone administration of 2403 mg/day.Of the fifteen patients, 12 had reported treatment emergent adverseevents of increased AST or ALT or hepatitis. The liver function testelevations for the remaining three patients were not documented as anadverse event (discussed below).

Of the twelve patients, two patients received continued administrationof pirfenidone at the full daily dose of 2403 mg/day. The liver functiontest of one patient resolved to a Grade 0. The other patient had ahistory of steatosis and a Grade 1 abnormality prior to pirfenidonetreatment and underwent a dose reduction for unrelated reasons (rash anddiarrhea), not for abnormal liver function tests, and ended the studywith a Grade 1 elevation.

Two patients had a temporary dose reduction or a temporarydiscontinuation of pirfenidone, and were rechallenged and escalated backto full dose. They completed the study at the full dose of 2403 mg/daywith normal liver enzymes.

Seven patients underwent a permanent dose reduction of pirfenidone, insome cases after a temporary discontinuation of drug; by completion ofthe study, 3 patients were receiving 801 mg/day and 4 patients werereceiving 1602 mg/day. With the exception of one patient, rechallengewith a higher dose was not attempted with these patients. The patientthat was rechallenged received the full dose of 2403 mg/day, but thedose was later reduced due to a recurrence of Grade 2 elevation in ALTlevels. All seven patients completed the study with resolution oftransaminases, except for one patient that had a Grade 1 elevation atstudy completion.

One patient discontinued treatment due to abnormal liver function testsin AST and/or ALT levels. The dose for this patient was initiallydecreased to 1602 mg/day, then discontinued, and then resumed at 1602mg/day. For this patient, however, treatment was permanentlydiscontinued because a Grade 2 elevation of AST coincided with a Grade 3ALT elevation in liver function tests.

Of the three patients whose liver function test elevations were notdocumented as an adverse event, one had Grade 1 AST and ALT elevation atbaseline, and experienced a Grade 1 elevation of AST at the lastdocumented assessment. This patient received no dose modification aftera Grade 2 elevation in AST and/or ALT levels. A second patient with aGrade 2 transaminase elevation had treatment temporarily discontinuedfor acute cerebral artery occlusion. Transaminase levels returned tonormal once the dose was escalated back to 2403 mg/day, and the patientcompleted the study on full dose with normal transaminases. The thirdpatient had no liver function test abnormalities while on treatmentuntil Day 422, then the patient experienced a Grade 2 AST and Grade 1ALT elevation with respiratory failure due to IPF. Study drug wasdiscontinued the same day for respiratory failure. The patient washospitalized on Day 434 and died on Day 439 due to respiratory failure.

Grade 3 Abnormalities in Liver Function

Four patients developed Grade 3 liver function abnormality in AST and/orALT levels after pirfenidone administration, all of who had a treatmentemergent adverse event of either increased AST and/or ALT. Two of thefour patients discontinued study drug for elevated liver function tests.In both instances, the abnormalities had not resolved, with Grade 2 andGrade 3 abnormalities last documented. The two other patients had Grade1 abnormalities at screening and/or baseline. One patient discontinuedfor lung transplant at which time the last documented values showed aGrade 1 abnormality. The other patient interrupted study drug(investigator decision), and subsequently discontinued study drug(sponsor decision). The AST and ALT elevations had normalized at thelast documented value.

The foregoing description is given for clearness of understanding only,and no unnecessary limitations should be understood therefrom, asmodifications within the scope of the invention may be apparent to thosehaving ordinary skill in the art. Although methods have been describedwith reference to particular embodiments, a person of ordinary skill inthe art will readily appreciate that other ways of performing the actsassociated with the methods may be used.

All patents, publications and references cited herein are hereby fullyincorporated by reference. In case of conflict between the presentdisclosure and incorporated patents, publications and references, thepresent disclosure should control.

What is claimed is:
 1. A method of administering pirfenidone to treat a patient who would benefit from pirfenidone administration, optionally a patient with idiopathic pulmonary fibrosis (IPF), said patient having exhibited a Grade 2 abnormality in one or more biomarkers of liver function after pirfenidone administration, comprising (a) administering to said patient pirfenidone at doses of at least 1600 mg/day or 1602 mg/day.
 2. A method of claim 1 comprising (a) administering to said patient pirfenidone at doses of 2400 mg/day or 2403 mg/day.
 3. The method of claim 1 or 2 further comprising, prior to step (a), administering to said patient pirfenidone at doses lower than 2400 mg/day for a time period.
 4. The method of any of claims 1-3 wherein prior to step (a) pirfenidone is discontinued until biomarkers of liver function are within normal limits.
 5. The method of any of claims 1-4 further comprising, prior to step (a), administering about 1600 mg/day or 1602 mg/day pirfenidone for a period of time, optionally about one week, or until biomarkers of liver function are within normal limits.
 6. The method of any of claims 1-5 further comprising, prior to step (a), administering about 800 mg/day or 801 mg/day pirfenidone for a period of time, optionally about one week, or until biomarkers of liver function are within normal limits, followed by administering about 1600 mg/day or 1602 mg/day pirfenidone for a period of time, optionally about one week, or until biomarkers of liver function are within normal limits.
 7. The method of any of claims 1-6 further comprising, prior to step (a), discontinuing pirfenidone for a period of time, optionally about one week, or until biomarkers of liver function are within normal limits.
 8. The method of any of claims 1-7, wherein the pirfenidone is administered three times per day with food.
 9. The method of any of claims 1-8, wherein said one or more biomarkers of liver function is selected from the group consisting of alanine transaminase, aspartate transaminase, and bilirubin.
 10. The method of any of claims 1-9 further comprising the step of measuring one or more biomarkers of liver function.
 11. The method of any of claims 1-10, wherein said one or more biomarkers of liver function are alanine transaminase and aspartate transaminase.
 12. Pirfenidone for use in treating a patient who would benefit from pirfenidone administration, optionally a patient with idiopathic pulmonary fibrosis (IPF), said patient having exhibited a Grade 2 abnormality in one or more biomarkers of liver function after pirfenidone administration, wherein (a) said patient is administered pirfenidone at doses of 2400 mg/day or 2403 mg/day.
 13. Pirfenidone for use in treating a patient according to claim 11, wherein, prior to step (a), said patient is administered pirfenidone at doses lower than 2400 mg/day for a time period.
 14. Pirfenidone for use in treating a patient according to claim 11 or 12, wherein, prior to step (a), pirfenidone administration to the patient is discontinued for a time period, optionally about one week, or until biomarkers of liver function are within normal limits.
 15. Pirfenidone for use in treating a patient according to any of claims 11-13, wherein, prior to step (a), about 1600 mg/day or 1602 mg/day pirfenidone is administered to the patient for a time period, optionally about one week, or until biomarkers of liver function are within normal limits.
 16. Pirfenidone for use in treating a patient according to any of claims 11-14, wherein, prior to step (a), about 800 mg/day or 801 mg/day pirfenidone is administered to the patient for a time period, optionally about one week, or until biomarkers of liver function are within normal limits, and then about 1600 mg/day or 1602 mg/day pirfenidone is administered to the patient for a time period, optionally about one week or until biomarkers of liver function are within normal limits.
 17. Pirfenidone for use in treating a patient according to any of claims 11-15, wherein, prior to step (a), administration of pirfenidone is discontinued for a time period, optionally about one week, or until biomarkers of liver function are within normal limits, and then about 800 mg/day or 801 mg/day pirfenidone is administered for a time period, optionally about one week or until biomarkers of liver function are within normal limits, and then about 1600 mg/day or 1602 mg/day pirfenidone is administered for a time period, optionally about one week or until biomarkers of liver function are within normal limits.
 18. Pirfenidone for use in treating a patient according to any of claims 11-16, wherein the pirfenidone is administered three times per day with food.
 19. Pirfenidone for use in treating a patient according to any of claims 11-17, wherein said one or more biomarkers of liver function is selected from the group consisting of alanine transaminase, aspartate transaminase, and bilirubin.
 20. Pirfenidone for use in treating a patient according to any of claims 11-18 further comprising measuring one or more biomarkers of liver function.
 21. Pirfenidone for use in treating a patient according to any of claims 11-19, wherein said one or more biomarkers of liver function are alanine transaminase and aspartate transaminase.
 22. Use of pirfenidone in the manufacture of a medicament for treating a patient who would benefit from pirfenidone administration, optionally a patient with idiopathic pulmonary fibrosis (IPF), said patient having exhibited a Grade 2 abnormality in one or more biomarkers of liver function after pirfenidone administration, wherein (a) said patient is administered pirfenidone at doses of 2400 mg/day or 2403 mg/day.
 23. Use according to claim 21, wherein, prior to step (a), said patient is administered pirfenidone at doses lower than 2400 mg/day for a time period.
 24. Use according to claim 21 or 22, wherein, prior to step (a), pirfenidone administration to the patient is discontinued for a time period, optionally about one week or until biomarkers of liver function are within normal limits.
 25. Use according to any of claims 21-23, wherein, prior to step (a), about 1600 mg/day or 1602 mg/day pirfenidone is administered to the patient for a time period, optionally about one week, or until biomarkers of liver function are within normal limits.
 26. Use according to any of claims 21-24, wherein, prior to step (a), about 800 mg/day or 801 mg/day pirfenidone is administered to the patient for a time period, optionally about one week, or until biomarkers of liver function are within normal limits, and then about 1600 mg/day or 1602 mg/day pirfenidone is administered to the patient for a time period, optionally about one week, or until biomarkers of liver function are within normal limits.
 27. Use according to any of claims 21-25, wherein, prior to step (a), administration of pirfenidone is discontinued for a time period, optionally about one week, or until biomarkers of liver function are within normal limits, and then about 800 mg/day or 801 mg/day pirfenidone is administered for a time period, optionally about one week or until biomarkers of liver function are within normal limits, and then about 1600 mg/day or 1602 mg/day pirfenidone is administered for a time period, optionally about one week or until biomarkers of liver function are within normal limits.
 28. Use according to any of claims 21-26, wherein the pirfenidone is administered three times per day with food.
 29. Use according to any of claims 21-27, wherein said one or more biomarkers of liver function is selected from the group consisting of alanine transaminase, aspartate transaminase, and bilirubin.
 30. Use according to any of claims 21-28 further comprising measuring one or more biomarkers of liver function during administration of pirfenidone.
 31. Use according to any of claims 21-29, wherein said one or more biomarkers of liver function are alanine transaminase and aspartate transaminase.
 32. The method according to claim 1, wherein, prior to step (a), said patient is administered pirfenidone at doses lower than 1600 mg/day for a time period.
 33. The method according to claim 1 or 32, wherein, prior to step (a), pirfenidone administration to the patient is discontinued for a time period, optionally about one week or until biomarkers of liver function are within normal limits.
 34. The method according to any of claim 1 or 32-33, wherein, prior to step (a), about 800 mg/day or 801 mg/day pirfenidone is administered to the patient for a time period, optionally about one week, or until biomarkers of liver function are within normal limits.
 35. The method according to any of claim 1 or 32-34, wherein the pirfenidone is administered three times per day with food.
 36. The method according to any of claim 1 or 32-35, wherein said one or more biomarkers of liver function is selected from the group consisting of alanine transaminase, aspartate transaminase, and bilirubin.
 37. The method according to any of claim 1 or 32-36 further comprising measuring one or more biomarkers of liver function during administration of pirfenidone.
 38. The method according to any of claim 1 or 32-37, wherein said one or more biomarkers of liver function are alanine transaminase and aspartate transaminase.
 39. Pirfenidone for use in treating a patient who would benefit from pirfenidone administration, optionally a patient with idiopathic pulmonary fibrosis (IPF), said patient having exhibited a Grade 2 abnormality in one or more biomarkers of liver function after pirfenidone administration, wherein (a) said patient is administered pirfenidone at doses of at least 1600 mg/day or 1602 mg/day.
 40. Pirfenidone for use in treating a patient according to claim 39, wherein, prior to step (a), said patient is administered pirfenidone at doses lower than 1600 mg/day for a time period.
 41. Pirfenidone for use in treating a patient according to claim 39 or 40, wherein, prior to step (a), pirfenidone administration to the patient is discontinued for a time period, optionally about one week or until biomarkers of liver function are within normal limits.
 42. Pirfenidone for use in treating a patient according to any of claims 39-41, wherein, prior to step (a), about 800 mg/day or 801 mg/day pirfenidone is administered to the patient for a time period, optionally about one week, or until biomarkers of liver function are within normal limits.
 43. Pirfenidone for use in treating a patient according to any of claims 39-42, wherein the pirfenidone is administered three times per day with food.
 44. Pirfenidone for use in treating a patient according to any of claims 39-43, wherein said one or more biomarkers of liver function is selected from the group consisting of alanine transaminase, aspartate transaminase, and bilirubin.
 45. Pirfenidone for use in treating a patient according to any of claims 39-44 further comprising measuring one or more biomarkers of liver function during administration of pirfenidone.
 46. Pirfenidone for use in treating a patient according to any of claims 39-45, wherein said one or more biomarkers of liver function are alanine transaminase and aspartate transaminase.
 47. Use of pirfenidone in the manufacture of a medicament for treating a patient who would benefit from pirfenidone administration, optionally a patient with idiopathic pulmonary fibrosis (IPF), said patient having exhibited a Grade 2 abnormality in one or more biomarkers of liver function after pirfenidone administration, wherein (a) said patient is administered pirfenidone at doses of at least 1600 mg/day or 1602 mg/day.
 48. The use according to claim 47, wherein, prior to step (a), said patient is administered pirfenidone at doses lower than 1600 mg/day for a time period.
 49. The use according to claim 47 or 48, wherein, prior to step (a), pirfenidone administration to the patient is discontinued for a time period, optionally about one week or until biomarkers of liver function are within normal limits.
 50. The use according to any of claims 47-49, wherein, prior to step (a), about 800 mg/day or 801 mg/day pirfenidone is administered to the patient for a time period, optionally about one week, or until biomarkers of liver function are within normal limits.
 51. The use according to any of claims 47-50, wherein the pirfenidone is administered three times per day with food.
 52. The use according to any of claims 47-51, wherein said one or more biomarkers of liver function is selected from the group consisting of alanine transaminase, aspartate transaminase, and bilirubin.
 53. The use according to any of claims 47-52 further comprising measuring one or more biomarkers of liver function during administration of pirfenidone.
 54. The use according to any of claims 47-53, wherein said one or more biomarkers of liver function are alanine transaminase and aspartate transaminase.
 55. The method or use of any of the preceding claims, wherein the patient who would benefit from pirfenidone administration suffers from a condition selected from the group consisting of pulmonary fibrosis, idiopathic interstitial pneumonia, autoimmune lung diseases, benign prostate hypertrophy, coronary or myocardial infarction, atrial fibrillation, cerebral infarction, myocardiac fibrosis, musculoskeletal fibrosis, post-surgical adhesions, liver cirrhosis, renal fibrotic disease, fibrotic vascular disease, scleroderma, Hermansky-Pudlak syndrome, neurofibromatosis, Alzheimer's disease, diabetic retinopathy, skin lesions, and lymph node fibrosis associated with HIV.
 56. The method or use of any of the preceding claims wherein the patient who would benefit from pirfenidone administration suffers from a condition selected from the group consisting of chronic obstructive pulmonary disease (COPD), inflammatory pulmonary fibrosis (IPF), rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gout, sepsis, septic shock, endotoxic shock, gram-negative sepsis, toxic shock syndrome, myofacial pain syndrome (MPS), Shigellosis, asthma, adult respiratory distress syndrome, inflammatory bowel disease, Crohn's disease, psoriasis, eczema, ulcerative colitis, glomerular nephritis, scleroderma, chronic thyroiditis, Grave's disease, Ormond's disease, autoimmune gastritis, myasthenia gravis, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, pancreatic fibrosis, chronic active hepatitis, acute and chronic renal disease, renal fibrosis, irritable bowel syndrome, pyresis, restenosis, cerebral malaria, stroke and ischemic injury, neural trauma, Huntington's disease, Parkinson's disease, acute and chronic pain, allergies, cardiac hypertrophy, chronic heart failure, acute coronary syndrome, cachexia, malaria, leprosy, leishmaniasis, Lyme disease, Reiter's syndrome, acute synoviitis, muscle degeneration, bursitis; tendonitis, tenosynoviitis, herniated, ruptured, or prolapsed intervertebral disk syndrome, osteopetrosis, thrombosis, silicosis, pulmonary sarcosis, bone resorption diseases, cancer, graft-versus-host reaction; and auto-immune diseases, AIDS, Herpes Zoster, Herpes Simplex I or II, influenza virus, Severe Acute Respiratory Syndrome (SARS), cytomegalovirus, and diabetes mellitus. 